Liver transplantation

Abstract

Purpose of reviewLong-term survival of liver transplant recipients is threatened by increased rates of de-novo malignancy and recurrence of hepatocellular carcinoma (HCC), both events tightly related to immunosuppression.Recent findingsThere is accumulating evidence linking increased exposure to immunosuppressants and carcinogenesis, particularly concerning calcineurin inhibitors (CNIs), azathioprine and antilymphocyte agents. A recent study including 219 HCC transplanted patients showed that HCC recurrence rates were halved if a minimization of CNIs was applied within the first month after liver transplant. With mammalian target of rapamycin (mTOR) inhibitors as approved immunosuppressants for liver transplant patients, pooled data from several retrospective studies have suggested their possible benefit for reducing HCC recurrence.SummaryRandomized controlled trials with sufficiently long follow-up are needed to evaluate the influence of different immunosuppression protocols in preventing malignancy after LT. Currently, early minimization of CNIs with or without mTOR inhibitors or mycophenolate seems a rational strategy for patients with risk factors for de-novo malignancy or recurrence of HCC after liver transplant. A deeper understanding of the immunological pathways of rejection and cancer would allow for designing more specific and safer drugs, and thus to prevent cancer after liver transplant.

Review on immunosuppression in liver transplantation

“…CNIs possess prooncogenic effects as documented in experimental models and also in clinical trials both retrospective and prospective [64] . Both tacrolimus and cyclosporine are associated with increased risk of de novo malignancies in solid organ transplantation.…”

“…Dividing the dose to a four times a day schedule may be helpful; however, more serious adverse GI effects as inflammatory bowel disease-like colitis and graft vs host disease-like enteropathy related to MPA have been reported [61,62] . MPA seems to have a protective effect against post transplant de novo malignancies and when included in immunosuppression regimens may increase the time to develop malignancies [63] , however, MPA was not shown to be effective in prevention of post liver transplant recurrence of HCC [64] .…”

“…Both tacrolimus and cyclosporine are associated with increased risk of de novo malignancies in solid organ transplantation. The risk of post liver transplant HCC recurrence has been shown to be related to the high blood levels of CNIs, particularly in the early post transplant period rather than the type of CNI [64,101] . The results of studies comparing the effect of the type of CNI (cyclosporine vs tacrolimus) are conflicting and it seems that the role of dosage and blood levels of CNIs is more important than the choice of agent [64,101,102] .…”

“…The risk of post liver transplant HCC recurrence has been shown to be related to the high blood levels of CNIs, particularly in the early post transplant period rather than the type of CNI [64,101] . The results of studies comparing the effect of the type of CNI (cyclosporine vs tacrolimus) are conflicting and it seems that the role of dosage and blood levels of CNIs is more important than the choice of agent [64,101,102] . Anti-lymphocyte antibodies which are increasingly used for induction of immunosuppression or treatment of steroid resistant rejections are also of concern for increasing the risk of post transplant HCC recurrence.…”

“…Its protective effect on post liver transplant HCC has not been sufficiently investigated in clinical trials, although reduced recurrence rate has been reported [72] . mTORIs are also possibly beneficial when included in immunosuppression regimen in recipients with malignancies other than HCC, but its use for this purpose needs to be explored by further studies [64] . The common adverse side effects related to mTORIs are edema, hyperlipidemia and oral ulcers.…”